U.S. patent application number 09/753095 was filed with the patent office on 2002-09-05 for hydrophilic polymeric material for coating biosensors.
Invention is credited to Cochran, Brooks B., Ponder, Bill C., Vachon, David J..
Application Number | 20020123087 09/753095 |
Document ID | / |
Family ID | 25029139 |
Filed Date | 2002-09-05 |
United States Patent
Application |
20020123087 |
Kind Code |
A1 |
Vachon, David J. ; et
al. |
September 5, 2002 |
Hydrophilic polymeric material for coating biosensors
Abstract
Disclosed is a biocompatible membrane comprising a hydrophilic
polyurea composition. The hydrophilic polyutea composition
comprises the product of a reaction mixture comprising (a) an amino
terminated polysiloxane, (b) a hydrophilic polymer selected from
the group consisting of a diamino terminated copolymer of
polypropylene glycol and polyethylene glycol, polyethylene glycol,
polypropylene glycol and diamino polyethylene glycol having an
average molecular weight of from about 400 to about 2000, and (c) a
diisocyanate selected from the group consisting of
hexamethylene-1,6-diisocyanate, dicyclohexylmethane
4,4'-diisocyanate, and isophorone diisocyanate, and constituting
about 50 mole % of the reaction mixture. In this mixture, (a) and
(b) constitute a polymeric portion of the reaction mixture, and the
hydrophilic polyurea composition has a ratio of its diffusion
coefficient for oxygen to its diffusion coefficient for glucose of
from about 2,000 to about 10,000. Also provided are biosensors
coated with a membrane of the invention, and methods of using such
biosensors to measure an analyte in a tissue of a subject.
Inventors: |
Vachon, David J.; (Granada
Hills, CA) ; Cochran, Brooks B.; (Sylmar, CA)
; Ponder, Bill C.; (Valencia, CA) |
Correspondence
Address: |
GATES & COOPER LLP
HOWARD HUGHES CENTER
6701 CENTER DRIVE WEST, SUITE 1050
LOS ANGELES
CA
90045
US
|
Family ID: |
25029139 |
Appl. No.: |
09/753095 |
Filed: |
December 29, 2000 |
Current U.S.
Class: |
435/14 ;
525/54.1 |
Current CPC
Class: |
Y10T 428/31551 20150401;
Y10T 428/31663 20150401; C08G 18/5024 20130101; C08G 18/6685
20130101; C09D 175/02 20130101; C12Q 1/002 20130101; C08G 18/61
20130101 |
Class at
Publication: |
435/14 ;
525/54.1 |
International
Class: |
C12Q 001/54; C08G
077/32; C08G 077/388 |
Claims
What is claimed is:
1. A biocompatible membrane comprising a hydrophilic polyurea
composition comprising the product of a first reaction mixture
comprising: (a) an amino terminated polysiloxane; (b) a hydrophilic
polymer selected from the group consisting of a diamino terminated
copolymer of polypropylene glycol and polyethylene glycol,
polyethylene glycol, polypropylene glycol and diamino polyethylene
glycol having an average molecular weight of from about 400 to
about 2000; and (c) a diisocyanate selected from the group
consisting of hexamethylene-1,6-diisocyanate, dicyclohexylmethane
4,4'-diisocyanate, and isophorone diisocyanate, and constituting
about 50 mole % of the reaction mixture; wherein (a) and (b)
constitute a polymeric portion of the first reaction mixture, and
wherein the hydrophilic polyurea composition has a ratio of its
diffusion coefficient for oxygen to its diffusion coefficient for
glucose of from greater than 2,000 to about 10,000.
2. The biocompatible membrane of claim 1, wherein the hydrophilic
polyurea composition further comprises the product of blend of the
first reaction mixture and a second reaction mixture, wherein the
second reaction mixture comprises (a), (b) and (c).
3. The biocompatible membrane of claim 1, wherein the hydrophilic
polyurea composition has a ratio of its diffusion coefficient for
oxygen to its diffusion coefficient for glucose of from about 3,000
to about 7,000.
4. The biocompatible membrane of claim 1, wherein the hydrophilic
polyurea composition has a ratio of its diffusion coefficient for
oxygen to its diffusion coefficient for glucose of from about 5,000
to about 7,000.
5. The biocompatible membrane of claim 1, wherein the hydrophilic
polymer comprises a polypropylene glycol)-block-poly(ethylene
glycol) bis(2-aminopropyl ether).
6. The biocompatible membrane of claim 1, wherein the polysiloxane
has a molecular weight of from about 500 to about 3,500.
7. The biocompatible membrane of claim 6, wherein the polysiloxane
has a molecular weight of about 2,500.
8. The biocompatible membrane of claim 1, wherein the mixture
further comprises a chain extender.
9. The biocompatible membrane of claim 8, wherein the chain
extender is selected from the group consisting of N-methyl
diethanolamine, ethylene diamine, butane diol, diethylene glycol,
propane diol and water.
10. The biocompatible membrane of claim 1, wherein the mixture has
a glucose diffusion coefficient of from about 1.times.10.sup.-9
cm.sup.2/s to about 200.times.10.sup.-9 cm.sup.2/s at 37.degree.
C.
11. The biocompatible membrane of claim 1, wherein the mixture has
a glucose diffusion coefficient of from about 2.5 .times.10.sup.-9
cm.sup.2/s to about 10.times.10.sup.-9 cm.sup.2/s at 37.degree.
C.
12. The biocompatible membrane of claim 1, wherein the polysiloxane
content is from about 15 mole percent to about 75 mole percent of
the polymeric portion of the mixture.
13. The biocompatible membrane of claim 1, wherein the polysiloxane
content is about 50 mole percent of the polymeric portion of the
mixture.
14. The biocompatible membrane of claim 1, wherein the hydrophilic
polymer comprises a combination of a diamino terminated copolymer
of polypropylene glycol and polyethylene glycol having an average
molecular weight of about 600; and a diamino terminated copolymer
of polypropylene glycol and polyethylene glycol having an average
molecular weight of about 900.
15. The biocompatible membrane of claim 14, wherein the diamino
terminated copolymer of polypropylene glycol and polyethylene
glycol comprises a polypropylene glycol)-block-poly(ethylene
glycol) bis(2-aminopropyl ether).
16. The biocompatible membrane of claim 1, wherein the polymeric
portion of the mixture comprises about 50 mole percent
polysiloxane, about 25 mole percent hydrophilic polymer having an
average molecular weight of about 600, and about 25 mole percent
hydrophilic polymer having an average molecular weight of about
900.
17. The biocompatible membrane of claim 16, wherein the hydrophilic
polymer comprises a diamino terminated copolymer of polypropylene
glycol and polyethylene glycol.
18. The biocompatible membrane of claim 17, wherein the diamino
terminated copolymer of polypropylene glycol and polyethylene
glycol comprises a polypropylene glycol)-block-poly(ethylene
glycol) bis(2-aminopropyl ether).
19. An implantable biosensor for measuring an analyte in biological
tissue, the biosensor having a coating adhered thereto, the coating
comprising a biocompatible membrane of claim 1.
20. The implantable biosensor of claim 19, further comprising a
transducer that generates a signal upon contact with the
analyte.
21. The implantable biosensor of claim 20, wherein the analyte is
glucose and the transducer is glucose oxidase.
22. A method of measuring an analyte in a tissue of a subject, the
method comprising introducing an implantable biosensor of claim 20
into the tissue of the subject and detecting the signal generated
by the transducer, wherein the amount of signal corresponds to the
amount of analyte.
23. The method of claim 22, wherein the analyte is glucose and the
transducer is glucose oxidase.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] This invention relates generally to polymeric materials and
to methods of making and using such materials. The polymeric
materials are hydrophilic, biocompatible, and suitable for use with
biosensors, such as glucose sensors.
BACKGROUND OF THE INVENTION
[0002] Biosensors are small devices that use biological recognition
properties for selective detection of various analytes or
biomolecules. Typically, the sensor will produce a signal that is
quantitatively related to the concentration of the analyte. To
achieve a quantitative signal, a recognition molecule or
combination of molecules is often immobilized at a suitable
transducer, which converts the biological recognition event into a
quantitative response.
[0003] The need for the continuous monitoring of biological markers
(analytes) in medicine has sparked a tremendous interest in the
study of biosensors in recent years. Without question, the greatest
interest has been geared toward the development of sensors to
detect glucose. In particular, enzymatic (amperometric) glucose
electrodes have been studied in more detail than any other
biosensors. Electroenzymatic biosensors use enzymes to convert a
concentration of analyte to an electrical signal. Immunological
biosensors rely on molecular recognition of an analyte by, for
example, antibodies. Chemoreceptor biosensors use chemoreceptor
arrays such as those of the olfactory system or nerve fibers from
the antennules of the blue crab Callinectes sapidus to detect the
presence of amino acids in concentrations as low as 10.sup.9 M. For
a review of some of the operating principles of biosensors, see
Bergveld, et al., Advances in Biosensors, Supplement 1, p. 31-91,
Turner ed., and Collison, et al., Anal. Chem. 62:425-437
(1990).
[0004] Regardless of the type of biosensor, each will possess
certain properties to function in vivo and provide an adequate
signal. First, the elements of the biosensor should be compatible
with the tissue to which it is attached, and be adequately safe
such that allergic or toxic effects ate not exerted. Further, the
sensor should be shielded from the environment to control drift in
the generated signal. Finally, the sensor should accurately measure
the analyte in the presence of proteins, electrolytes and
medications, which may have the potential to interfere.
[0005] The biosensor of interest is an amperometric glucose sensor.
There are several reasons for the wide-ranging interest in glucose
sensors. In the healthcare arena, enzymatic glucose test strips ate
useful for monitoring the blood sugar of patients with diabetes
mellitus. A sensor that has the ability to continuously monitor the
blood, or interstitial glucose of a person with diabetes could
provide great insight into the level of control that they have over
their disease and avoid the need for repeated blood draws.
Additionally, a continuously monitoring glucose sensor is one of
the critical components necessary for the development of an
artificial pancreas. To make such a system possible, a reliable
glucose sensor must communicate with an insulin pump.
[0006] An additional commercial application of this technology
focuses on sensors that can be used to monitor fermentation
reactions in the biotechnology industry. From a scientific and
commercial standpoint, interest has grown beyond glucose to other
analytes for the diagnosis of numerous medical conditions other
than diabetes.
[0007] Amperometric glucose sensors and oxido-reductase enzymes
that use O.sub.2 as a co-substrate, and are designed for
subcutaneous or intravenous use, typically require both an outer
membrane and an anti-interference membrane. The necessity for two
distinct membranes is largely due to the fundamental nature of the
sensor, as well as the environment in which the measurement is
made.
[0008] A glucose sensor works by a reaction in which glucose reacts
with oxygen in the presence of glucose oxidase (GOd) to form
gluconolactone and hydrogen peroxide. The gluconolactone further
reacts with water to hydrolyze the lactone ring and produce
gluconic acid. The H.sub.2O.sub.2 formed is electrochemically
oxidized at an electrode as shown below (Equation 1):
H.sub.2O.sub.2.fwdarw.O.sub.2+2.sub.e+2H.sup.+ (1)
[0009] The current measured by the sensor/potentiostat (+0.5 to
+0.7 v oxidation at Pt black electrode) is the result of the two
electrons generated by the oxidation of the H.sub.2O.sub.2.
Alternatively, one can measure the decrease in the oxygen by
amperometric measurement 0.5 to -1 V reduction at a Pt black
electrode).
[0010] The stoichiometry of the GOd reaction points to a challenge
of developing a reliable glucose sensor. If oxygen and glucose are
present in equimolar concentrations, then the H.sub.2O.sub.2 is
stoichiometrically related to the amount of glucose that reacts at
the enzyme. In this case, the ultimate current is also proportional
to the amount of glucose that reacts with the enzyme. If there is
insufficient oxygen for all of the glucose to react with the
enzyme, then the current will be proportional to the oxygen
concentration, not the glucose concentration. For the sensor to be
a true glucose sensor, glucose must be the limiting reagent, i.e.
the O.sub.2 concentration must be in excess for all potential
glucose concentrations. For example, the glucose concentration in
the body of a diabetic patient can vary from 2 to 30 mM (millimoles
per liter or 36 to 540 mg/dl), whereas the typical oxygen
concentration in the tissue is 0.02 to 0.2 mM (see, Fisher, et al.,
Biomed. Biochem. Acta. 48:965-971 (1989). This ratio in the body
means that the sensor would be running in the Michaelis Menten
limited regime and would be very insensitive to small changes in
the glucose concentration. This problem has been called the "oxygen
deficit problem". Accordingly, a method or system must be devised
to either increase the O.sub.2 in the GOd enzyme layer, decrease
the glucose concentration, or devise a sensor that does not use
O.sub.2.
[0011] There is a need for a glucose sensor having a biocompatible
membrane with an improved ratio of its oxygen permeability to it
glucose permeability, and that offers physical and biological
stability and strength, adhesion to the substrate, processibility
(i.e. solubility in common organic solvents for the development of
coatings from polymer lacquer and the ability to cut using laser
ablation or other large scale processing method), the ability to be
synthesized and manufactured in reasonable quantities and at
reasonable prices,, and compatibility with the enzyme as deposited
on the sensor. The present invention fulfills these needs and
provides other related advantages.
SUMMARY OF THE INVENTION
[0012] The invention provides a biocompatible membrane comprising a
hydrophilic polyurea composition. The hydrophilic polyurea
composition comprises the product of a reaction mixture comprising
(a) an amino terminated polysiloxane, (b) a hydrophilic polymer
selected from the group consisting of a diamino terminated
copolymer of polypropylene glycol and polyethylene glycol,
polyethylene glycol, polypropylene glycol and diamino polyethylene
glycol having an average molecular weight of from about 400 to
about 2000, and (c) a diisocyanate selected from the group
consisting of hexamethylene-1,6-diisocyanate, dicyclohexylmethane
4,4'-diisocyanate, and isophorone diisocyanate, and constituting
about 50 mole % of the reaction mixture. In this mixture, (a) and
(b) constitute a polymeric portion of the reaction mixture, and
when the mixture is reacted with (c), the end product polymer has a
ratio of its diffusion coefficient for oxygen to its diffusion
coefficient for glucose of from about 2,000 to about 10,000. In a
preferred embodiment, the hydrophilic polyurea composition has a
ratio of its diffusion coefficient for oxygen to its diffusion
coefficient for glucose of from about 3,000 to about 7,000. In a
more preferred embodiment, the hydrophilic polyurea composition has
a ratio of its diffusion coefficient for oxygen to its diffusion
coefficient for glucose of from about 5,000 to about 7,000.
[0013] The biocompatible membrane of the invention can include a
hydrophilic polymer that comprises a polypropylene
glycol)-block-poly(ethylene glycol) bis(2-aminopropyl ether). The
polysiloxane preferably has a molecular weight of about 500 to
about 3,500, and most preferably, about 2,500. In some embodiments,
the reaction mixture further comprises a chain extender, such as
N-methyl diethanolamine, ethylene diamine, butane diol, diethylene
glycol, propane diol or water. The biocompatible membrane of the
invention can be the product of a mixture having a glucose
diffusion coefficient of from about 1.times.10.sup.-9 cm.sup.2/s to
about 200.times.10.sup.-9 cm.sup.2/s at 37.degree. C., or
preferably, from about 2.5.times.10.sup.-9 cm.sup.2/s to about
10.times.10.sup.-9 cm.sup.2/s at 37.degree. C.
[0014] In a preferred embodiment, the polysiloxane content is from
about 15 mole percent to about 75 mole percent of the polymeric
portion of the mixture, or more preferably, about 50 mole percent
of the polymeric portion of the mixture. In one embodiment, the
hydrophilic polymer comprises a combination of a diamino terminated
copolymer of polypropylene glycol and polyethylene glycol having an
average molecular weight of about 600 and a diamino terminated
copolymer of polypropylene glycol and polyethylene glycol having an
average molecular weight of about 900. In another embodiment, the
polymeric portion of the mixture comprises about 50 mole percent
polysiloxane, about 25 mole percent hydrophilic polymer having an
average molecular weight of about 600, and about 25 mole percent
hydrophilic polymer having an average molecular weight of about
900. Preferably, the hydrophilic polymer comprises a diamino
terminated copolymer of polypropylene glycol and polyethylene
glycol. A preferred diamino terminated copolymer of polypropylene
glycol and polyethylene glycol is poly(propylene
glycol)-block-poly(ethylene glycol) bis(2-aminopropyl ether).
[0015] The invention further provides an implantable biosensor for
measuring an analyte in biological tissue, the biosensor having a
coating comprising a biocompatible membrane of the invention. The
implantable biosensor can further comprise a transducer that
generates a signal upon contact with the analyte. In a preferred
embodiment, the analyte is glucose and the transducer is glucose
oxidase.
[0016] The invention additionally provides a method of measuring an
analyte in a tissue of a subject. The method comprises introducing
an implantable biosensor of the invention into the tissue of the
subject, and detecting the signal generated by the transducer. The
amount of signal corresponds to the amount of analyte. Preferably,
the analyte is glucose and the transducer is glucose oxidase.
BRIEF DESCRIPTION OF THE DRAWING
[0017] FIG. 1 is a schematic illustration of polymer formation
using water as a chain extender and starting with a polyol diamine,
a polysiloxane diamine and hexamethylene diisocyanate.
DETAILED DESCRIPTION
[0018] All scientific and technical terms used in this application
have meanings commonly used in the art unless otherwise specified.
As used in this application, the following words or phrases have
the meanings specified.
[0019] As used herein, the term "polyurea" refers to a polymer
containing urea linkages. Such polymers may additionally contain
urethane linkages. Typically, such polymers are formed by combining
diisocyanates with amines and/or alcohols. For example, combining
isophorone diisocyanate with PEG 600 and aminopropyl polysiloxane
under polymerizing conditions provides a polyurethane/polyurea
composition having both urethane (carbamate) linkages and urea
linkages.
[0020] As used herein, "adhered to" or "adhered thereto" means
stuck to or fused with such that a substance adhered to a surface
remains substantially attached to or closely associated with the
surface.
[0021] As used herein, "a" or "an" means at least one, and unless
clearly indicated otherwise, includes a plurality.
Overview
[0022] The invention provides hydrophilic glucose limiting
polymeric materials that offer improved hydration and faster
response times. The superior hydration characteristics of the
polymeric materials provide improved biocompatibility and
resistance to biofouling. The increased hydrophilicity of the
material provides a polymer that can be coated onto a biosensor
without requiring a second coating to enhance surface wetting of
the device. In addition, the invention offers polymeric materials
whose overall polymeric structure can be controlled by use of a
diamine or diol chain extender instead of water. The invention
additionally provides polymer blends that offer advantageous
features over individual polymeric materials that can be selected
in accordance with desired characteristics. Also provided are
biosensors having a biocompatible membrane of the invention adhered
thereto, and methods of measuring an analyte in a tissue of a
subject using such a biosensor.
[0023] Three characteristics of the biocompatible membranes of the
invention that are of particular interest are glucose permeability,
oxygen permeability, and the thermal dependence of these
permeabilities. A preferred membrane has a permeability constant
for glucose mass transport through the material that approximates
5.0.times.10.sup.-9 cm.sup.2/s at 37.degree. C. Additionally, a
ratio of oxygen permeability to glucose permeability of greater
than about 3000 is preferred. Generally, the higher the
permeability ratio, the better, with the exception of a ratio of
infinity, which would result from a glucose permeability
approaching zero. Also preferred is a membrane that exhibits
minimal change in oxygen and glucose permeability in response to
temperature changes.
Biocompatible Membranes
[0024] A glucose sensor intended for in vivo use requires that the
supply of oxygen in the vicinity of the sensing element not be
depleted. Additionally, the glucose should diffuse to the sensor at
a controlled rate. Overall, the membrane should control the
relative rates of diffusion of oxygen and glucose to the sensor so
that the local concentration of oxygen is not depleted.
Additionally, glucose sensors intended for in vivo use must also be
biocompatible with the body, and they must be able to function in
an environment in which harsh inflammatory components brought on by
the process of tissue injury and healing are present. Furthermore,
these membranes must resist against the adhesion of biological
components (biofouling) such as cells and proteins that can
interfere with a sensor's performance. Thus, the enzyme(s) used in
such sensors must be protected from degradation or denaturation,
while the elements of such sensors must be protected from molecules
that would foul the sensors or their accuracy will decrease over
time.
[0025] In one aspect, the present invention provides a
biocompatible membrane comprising a hydrophilic polyurea
composition. The hydrophilic polyurea composition comprises the
product of a reaction mixture comprising (a) an amino terminated
polysiloxane, (b) a hydrophilic polymer selected from the group
consisting of a diamino terminated copolymer of polypropylene
glycol and polyethylene glycol, polyethylene glycol, polypropylene
glycol and diamino polyethylene glycol having an average molecular
weight of from about 400 to about 2000, and (c) a diisocyanate
selected from the group consisting of
hexamethylene-1,6-diisocyanate, dicyclohexylmethane
4,4'-diisocyanate, and isophorone diisocyanate, and constituting
about 50 mole % of the reaction mixture. In this mixture, (a) and
(b) constitute a polymeric portion of the reaction mixture, and the
hydrophilic polyurea composition has a ratio of its diffusion
coefficient for oxygen to its diffusion coefficient for glucose of
from greater than 2,000 to about 10,000. In a preferred embodiment,
the hydrophilic polyurea composition has a ratio of its diffusion
coefficient for oxygen to its diffusion coefficient for glucose of
from about 3,000 to about 7,000. In a more preferred embodiment,
the hydrophilic polyurea composition has a ratio of its diffusion
coefficient for oxygen to its diffusion coefficient for glucose of
from about 5,000 to about 7,000. The biocompatible membrane of the
invention can be the product of a mixture having a glucose
diffusion coefficient of from about 1.times.10.sup.-9 cm.sup.2/s to
about 200.times.10.sup.-9 cm.sup.2/s at 37.degree. C., or
preferably, from about 2.5.times.10.sup.-9 cm.sup.2/s to about
10.times.10.sup.-9 cm.sup.2/s at 37.degree. C.
Polymer Blends
[0026] The biocompatible membrane of the invention comprises a
combination of hydrophobic (polysiloxane) and hydrophilic polymers.
In a preferred embodiment, the hydrophilic polymer comprises
polyurea (see, e.g., U.S. Pat. Nos. 5,777,060 and 5,786,439, both
of which are incorporated herein by reference) and, optionally,
polyurethane as well. The membrane preferably includes a blend of
two or more polymers, each of which can comprise a combination of
two or more polymers with different characteristics, including
combinations of hydrophobic and hydrophilic polymers, yielding a
solid mixture or blend with desired glucose limiting and
performance properties.
[0027] In one embodiment, the hydrophilic polymer comprises a
diarnino terminated copolymer of polypropylene glycol and
polyethylene glycol. A preferred diamino terminated copolymer of
polypropylene glycol and polyethylene glycol, comprises
polypropylene glycol)-block-poly(ethylene glycol) bis(2-aminopropyl
ether). Suitable hydrophilic polymers for use in polymer blends of
the invention have average molecular weights in the range of from
about 400 to about 2000, and include poly(propylene
glycol)-block-poly(ethylene glycol) bis(2-aminopropyl ether)s
Jaeffamine.TM.; Huntsman Chemical) such as Jeffaminc 600 (J600),
having an average molecular weight (mw) of 600,and Jeffamine 900
(J900), having an average mw of 900; polyethylene glycols (PEGs),
such as PEG having an average mw of 600, 1000 or 2000 (PEG 600, PEG
1000, PEG 2000); polypropylene glycols (PPGs), such as PPG having
an average mw of 400; and diamino polyethylene glycol (DAPEG), such
as DAPEG 2000, having an average mw of 2000.
[0028] In a preferred embodiment, the polysiloxane content is from
about 15 mole % to about 75 mole % of the polymeric portion of the
mixture, or more preferably, about 50 mole % of the polymeric
portion of the mixture. A preferred polysiloxane has a molecular
weight of about 500 to about 3,500, with a molecular weight of
about 2,500 being most preferable. In one embodiment, the
hydrophilic polymer comprises a combination of J600 and J900. In
another embodiment, the polymeric portion of the mixture comprises
about 50 mole % polysiloxane, about 25 mole % hydrophilic polymer
having an average molecular weight of about 600, and about 25 mole
% hydrophilic polymer having an average molecular weight of about
900. Preferably, the hydrophilic polymer comprises a diamino
terminated copolymer of polypropylene glycol and polyethylene
glycol, such as poly (propylene glycol)-block-poly (ethylene
glycol) bis(2-aminopropyl ether) (Jaeffamine.upsilon.). Exemplary
polymeric compositions for use in the reaction mixture of the
invention and their permeability characteristics are described in
Table 1 (wherein "hp" refers to hydrophilic portion). Additional
preferred polymer combinations and their influence on sensor
characteristics are described in Table 2.
1 TABLE 1 Diffusion Signal Hydration Coefficient Intrinsic nA Min-
Thick- Desig- Initial Rate % (mm*h) Viscosity @ 100 Max ness nation
Composition (mg/min) Max x 10e.sup.-6 (mL/g) mg/dL (nA) R.sup.2
(.mu.m) 75/25 29 37 0.82 30 25-39 22- 0.997- 2.7 J600/PS510 62
0.999 936-53 85/15 52.5 46 1.64 20 70.1 59- 0.998 1.6 J600/PS510
105 936-11 hp-75/25 23 32 0.59 35 39.2 35.5- 1 3.8 J600/P600 42.4
936-15 hp-100J900 97 54 15.5 50 195.8 149- 0.974 2.3 236 936-22
hp-75/25 28.5 43 2.76 38 64 60.7- 0.999 3.6 J600/J900 71.5 936-42
hp-90/10 68.5 35 1.7 21 42.8 39.1- 0.998 2.8 J600/J900 47.1 985-67
hp-85/15 58 42 1.67 26 68.6 65-72 0.999 2.2 J600/J900 985-23
35/20/45 11 5 0.24 46 23.6 23.3- 1 2.6 J600/J900/ 24.1 PS510 985-79
75/25 51.5 38 1.33 16 49.2 43.5- 0.997 1.9 J600/PS510 56.6 w/EDA
Extension 2% Blend of 49 30 1.09 N/A 36.1 29.9- 0.999 2.5 75/25
J600/ 46.1 PS510 w/ hp-100J900 5% Blend 56.5 31.6 1.56 N/A 54.2
42.3- 0.999 2.1 76.6 11% Blend 62 31.9 1.32 N/A 49 44-55 0.998 2.2
15% Blend 60 37.3 1.52 N/A 58.8 54-62 0.998 2.3 20% Blend 65 36.7
1.92 N/A 57.6 32.4- 0.993 2.3 69.9 1001- 50/50 280.9 52 38.4 36 39
DAPEG2000/ PS510 2% Blend 51 28.5 36.3 34-40 1 2.6 of 75/25
J600/PS510 w/ 1/1 DAPEG2000/ PS510 5% Blend 54 21.5 43.5 41-45
0.999 2.5 15% Blend 58 11.7 61.9 58-67 0.999 2.5 927- hp:50% 15 37
0.06 46 12 10 to 0.999 1.8 34(76) peg600 14 927-40 hp:50% 77 98
9.23 39 103 100 0.997 un- peg1000 to even 108 927-43 hp:50% 60 47
3.88 40 136 117 0.993 1.8 jeff900 to 151 927-48 80% jeff600 52 39
2.32 23 32 28 to 0.998 2.5 35 927-52 hp:25% 24 21 0.54 31 26 23 to
0.999 1.7 ppg400 33 0.47 927-54 hp:50% 10 12 0.04 23 6 7 to 0.978
4.1 ppg400 32 986-17 65% jeff600 22 20 0.22 32 18 17 to 0.999 3.2
20 986-49 nmda/ 38 29 0.79 27 24 23 to 0.999 2.9 extension 25
986-63 10% excess 42 31 0.79 20 26 25 to 0.998 3.4 hmdi 35
Composition Theta (air) Theta (AI) Desig- Production Post- Post-
nation Material Dry Hydrated hydration Dry Hydrated hydration
936-53 85/15 109.1 97.9 106.8 113.1 95.3 104.2 J600/PS510 936-11
hp-75/25 100.1 98.6 107.8 103.4 105.3 109.8 J600/P600 936-15
hp-100J900 936-22 hp-75/25 J600/J900 936-42 hp-90/10 J600/J900
985-67 hp-85/15 103.9 106.2 105 112 109.1 108.7 J600/J900 985-23
35/20/45 93.6 105.4 J600/J900/ PS510 985-79 Production 108.1 105.9
111.4 106.2 Ration w/ EDA Extension 2% Blend of Production w/hp-
100 J900 5% Blend 11% Blend 15% Blend 20% Blend 107.2 105.2 93.8
102.7 1001- 50/50 109.1 79.3 105.4 103.5 51.2 105.4 39 DAPEG2000/
PS510
[0029]
2 TABLE 2 Percent Change Membrane Oxygen Glucose in Glucose
Composition Perm- Perm- Permeability Poly- eability eability
O.sub.2/Glucose from 37.degree. C. silox- Jeff Jeff (cm.sup.2/s)
(cm.sup.2/s) Permeability 27.degree. C. 42.degree. C. Polymer ane
900 600 x 10.sup.-5 x 10.sup.-9 Ratio (high) (low) A 50% 50% 2.9 27
1074 18% -19% B 50% 50% 2.0 Below N/A detection limit C 50% 25% 25%
2.3 4.4 5227 41% -15% D 75% 25% 2.2 Below N/A detection limit E 25%
75% 1 5.0 2000 64% -42% F 60 40 -- -- -- -- -- G 60 30 10 -- -- --
-- --
[0030] As shown in Table 2, glucose permeability is more affected
than oxygen permeability by changing the characteristics of the
hydrophilic component. In these examples, the hydrophilic component
is altered by varying the relative amounts of J600 and J900, the
latter of which is more hydrophilic than J600 by virtue of its
greater molecular weight. Polymer C is an illustration of how these
trends can be used to tailor glucose and oxygen permeabilities.
This material has the same fractional amount of polysiloxane (PS)
therefore maintaining good oxygen permeation. The hydrophilicity of
the polymer has been reduced (relative to a J900-PS polymer) by
using equimolar amounts of J900 andJ600. Because the hydrophilicity
has been decreased without compromising the oxygen permeability of
the polymer to a great extent, a material with a superior
oxygen/glucose permeability ratio is obtained.
[0031] Because the temperature of adipose tissue surrounding a
subcutaneous glucose sensor could be expected to range from roughly
30 to 40.degree. C., a polymer whose glucose permeability is
unaffected by temperature is desirable. Table 2 details the change
in glucose permeability (%) observed when cooling the sensor from
37.degree. C. to 27 .degree. C. or warming the sensor to 42
.degree. C. from 37 .degree. C. Interestingly, glucose permeability
drops with increasing temperature, whereas oxygen permeability
increases with temperature.
[0032] The inverse relationship between glucose permeability and
temperature is believed to be the result of the known lower
critical solution temperature (LCST) of many water-soluble
polyethers such as Jeffaine.TM. 600 and Jeffamine.TM. 900. The LCST
of aqueous solutions of these polymers is manifested by the fact
that these polymers are less soluble in water at higher
temperatures. Previous data have shown that glucose permeability
improves with increasing membrane hydrophilicity. Therefore, if
higher temperatures result in a less hydrated membrane due to the
LCST characteristics of the polyether segments of the membrane,
glucose permeability would also be lessened at higher
temperatures.
[0033] The data in the table below suggest materials with smaller
fractional polyether compositions are less subject to changes in
glucose permeability with changes in temperature. Furthermore,
polymers with higher Jeffamine.TM. 900 content in their hydrophilic
portion appear to have glucose permeabilities that are less
susceptible to changing temperature.
[0034] A polymer with greater than 50% PS content would be
beneficial due to the increased oxygen permeability and its reduced
susceptibility to temperature modulated glucose permeability.
However, the decreased hydrophilicity should be offset with the
addition of more Jeffaninet.TM. 900 than Jeffamine.TM. 600, as the
former promotes glucose permeability better than the latter and
appears to be less sensitive to thermal changes.
[0035] Polymer D, 75% PS-25% Jeff 900, did not show any glucose
permeability (O.sub.2 permeability was not measured). This suggests
that the PS content is best kept below about 75%. A material
comprising 60% PS and 40% Jeff 900 (F) may offer advantageous
properties. Additionally, 60% PS-30% Jeff 900-10% Jeff 600 (G)
would be an additional attractive alternative. Other alternatives
that should yield similar results include polymers incorporating
polyethylene glycol (PEG), polypropylene glycol (PPG),
amino-terminated PEG or PPG, as well as polymeric blends of the
polymers incorporating the above components, block copolymers
generated from the above components or blends of the above monomers
to yield random copolymeric structures.
[0036] In addition to the hydrophilic and hydrophobic polymers
described above, the reaction mixture comprises a diisocyanate,
which constitutes about 50 mole % of the reaction mixture. Examples
of diisocyanates include hexamethylene-1,6-diisocyanate (HMD1),
dicyclohexylmethane 4,4'-diisocyanate, and isophorone diisocyanate.
In some embodiments, 10% excess HMDI is included in the reaction
mixture. In some embodiments, the reaction mixture further
comprises a chain extender, such as N-methyl diethanolamine (NMDA),
ethylene diamine (EDA) or water (H.sub.2O).
[0037] Factors useful in selecting a polymeric composition for use
in a biocompatible membrane of the invention include hydration
rate, diffusion coefficient, and sensor performance and linearity.
Preferred compositions have an initial hydration rate (mg/min for a
5 minute period) at least equal to 29, a diffusion coefficient at
least equal to 0.82.times.10.sup.-6 mm h, and sensor performance in
100 mg/dL glucose solution of between 20 and 70 nA (more preferably
between 25 and 30 nA) with membrane thickness' (as measured by
reflectometry from a gold plated glass slide coated under the same
conditions as the sensors) that will allow for increasing coating
thickness in the case of high readings, and reducing thickness in
the case of low readings.
Biosensor
[0038] Biosensors typically include a transducer that generates a
signal upon contact with an analyte of interest. For example,
glucose sensors suitable for in vivo use can be prepared by
depositing a glucose sensitive enzyme, such as glucose oxidase,
onto an electrode via an electromotive plating process. The
substrate can be applied by immersion of the sensor in a bath
comprising glucose oxidase, a stabilizing protein, a surfactant and
a buffer for conductivity and stability of the protein solution,
and the enzyme is then deposited onto the electrode
potentiometrically. Alternatively, the substrate can be applied
using a microelectrogravimetric plating method, such as is
described in U.S. patent application Ser. No. 09/642,623.
[0039] The invention provides an implantable biosensor for
measuring an analyte of interest in biological tissue, the
biosensor having a coating comprising a biocompatible membrane of
the invention. The implantable biosensor can further comprise a
transducer that generates a signal upon contact with the analyte.
In a preferred embodiment, the analyte is glucose and the
transducer is glucose oxidase. Other enzymes can serve as
transducers as appropriate for the analyte of interest and examples
of such enzymes include, but are not limited to, lactate oxidase,
amino acid oxidase, glutathione, and reductase.
Methods
[0040] The invention additionally provides a method of measuring an
analyte in a tissue of a subject. The method comprises introducing
an implantable biosensor of the invention into the tissue of the
subject, and detecting the signal generated by the transducer. The
amount of signal corresponds to the amount of analyte. Preferably,
the analyte is glucose and the transducer is glucose oxidase.
[0041] The above description is illustrative and not restrictive.
Many variations of the invention will become apparent to those of
skill in the art upon review of this disclosure. Merely by way of
example a variety of solvents, membrane formation methods, and
other materials may be used without departing from the scope of the
invention. The scope of the invention should, therefore, be
determined not with reference to the above description, but instead
should be determined with reference to the appended claims along
with their full scope of equivalents. All publications, patents and
patent applications mentioned in this specification are herein
incorporated by reference into the specification to the same extent
as if each individual publication, patent or patent application was
specifically and individually indicated to be incorporated herein
by reference.
* * * * *